The Diabetes Branch of NIDDK has a long-standing interest in the etiology of severe insulin resistance. Initially, we have identified mutations in the insulin receptor gene and studied a group of patients with autoantibodies against the insulin receptor. More recently, we have concentrated on lipoatrophy syndromes: a group of heterogeneous syndromes characterized by lack of adipose tissue and severe insulin reisitance. In a collaboration with Dr. Abhimanyhu Garg (University of Texas Southwestern) and Anne Bowcock (University of Washington, St. Lois), we have reported mutations on the Lamin A/C gene in patients with an autosomal dominant form of familial partial lipodystrophy abd we have reported a linkage of congenital generalized lipodystrophy to chromosome 9q34. We are continuing our efforts to recruit new pedigrees in order to narrow the interval for the latter condition. We have completed a clinical study that demonstrated the efficacy of troglitazone in treatment of metabolic abnormalities in patients with various forms of lipodystrophy. This study also demonstrated that troglitazone increased body fat in these patients as well. The follow up of these patients are ongoing on a newer thiazolidinedione in order to determine if the increase in body will be incremental with prolonged exposure to thiazolidinedione compounds in these patients. More recently, we have initiated a novel research study thattests the efficacy of the adipocyte-derived leptin hormone replacement in ameliorating the metabolic abnormalities in lipoatrophy syndromes. This study provides a unique opportunity to study the peripheral effects of leptin on the muscle and liver, and preliminary results show a favorable response. While the major focus has been on lipaotrophy syndromes, we are continuing our efforts to understand the natural history of other severe insulin resistant states.